CN1720237A - 3h-quinazolin-4-one derivatives - Google Patents
3h-quinazolin-4-one derivatives Download PDFInfo
- Publication number
- CN1720237A CN1720237A CNA2003801052982A CN200380105298A CN1720237A CN 1720237 A CN1720237 A CN 1720237A CN A2003801052982 A CNA2003801052982 A CN A2003801052982A CN 200380105298 A CN200380105298 A CN 200380105298A CN 1720237 A CN1720237 A CN 1720237A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- benzyloxy
- quinazoline
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
Abstract
This invention relates to 3H-quinazolin-4-one derivatives as defined in the specification and claims, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as selective monoamine oxidase B inhibitors.
Description
The present invention relates to the 3H-quinazoline-4-one derivatives, they the preparation method, comprise their pharmaceutical composition and they are as the purposes of selectivity monoamine oxidase B inhibitors.
First aspect the invention provides the compound of formula I:
Wherein:
R
1For-(CH
2)
n-CO-NR
5R
6-(CH
2)
n-COOR
7-(CH
2)
n-NR
5R
6-(CH
2)
n-CN;-(CH
2)
n-OR
8Or phenyl, it is for unsubstituted or be selected from halogen and fluoro (C by 1 to 3
1-C
6The substituting group of)-alkyl replaces;
R
2Be hydrogen, halogen or C
1-C
6-alkyl;
R
3Be hydrogen, C
1-C
6-alkyl, C
3-C
6-cycloalkyl or benzyl;
R
4Be halogen, fluoro (C
1-C
6)-alkyl, cyano group, C
1-C
6-alkoxyl group or fluoro (C
1-C
6)-alkoxyl group;
R
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl;
R
7Be hydrogen or C
1-C
6-alkyl;
R
8Be hydrogen or C
1-C
6-alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
And their pharmacologically acceptable salt.
On the other hand, the invention provides the compound of formula I, wherein:
R
1For-(CH
2)
n-CO-NR
5R
6-(CH
2)
n-COOR
7-(CH
2)
n-NR
5R
6-(CH
2)
n-CN;-(CH
2)
n-OR
8Or phenyl, it is for unsubstituted or be selected from halogen and fluoro by 1 to 3
(C
1-C
6The substituting group of)-alkyl replaces;
R
2Be hydrogen or C
1-C
6-alkyl;
R
3Be hydrogen, C
1-C
6-alkyl, C
3-C
6-cycloalkyl or benzyl;
R
4Be halogen, fluoro (C
1-C
6)-alkyl, cyano group, C
1-C
6-alkoxyl group or fluoro (C
1-C
6)-alkoxyl group;
R
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl;
R
7Be hydrogen or C
1-C
6-alkyl;
R
8Be hydrogen or C
1-C
6-alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
And their pharmacologically acceptable salt.
The compound of having found general formula I is the selectivity monoamine oxidase B inhibitors.
(MAO EC1.4.3.4) is a kind of flavo-enzyme that contains to monoamine oxidase, is responsible for that for example phenyl-ethyl amine and many amine xenobiotics carry out oxidative deamination to endogenous monoamine neurotransmitter such as Dopamine HCL, serotonin, suprarenin or norepinephrine and trace amine.This enzyme exists with two kinds of forms, i.e. MAO-A and MAO-B, and they are by different genes encodings [Bach etc., Proc.Natl.Acad.Sci.USA 85:4934-4938 (1998)], and variant aspect tissue distribution, structure and substrate specificity.MAO-A has higher affinity to serotonin, octopamine, suprarenin and norepinephrine; And the natural substrate of MAO-B is phenyl-ethyl amine and tyrasamine.Think all oxidable Dopamine HCL of these two kinds of isoforms.MAO-B is distributed widely in [Cesura and Pletscher, Prog.Drug Research 38:171-297 (1992)] in a plurality of organs that comprise brain.As if the activity of brain MAO-B increase with age growth.This activity increase is by owing to the gliosis relevant with aging [Fowler etc., J.Neural.Transm.49:1-20 (1980)].In addition, the activity of the MAO-B [Dostert etc. that in the brain of patients with Alzheimer disease, significantly raise, Biochem.Pharmacol.38:555-561 (1989)], and found in its astroglia cell around the senile plaque by highly expression [Saura etc., Neuroscience 70:755-774 (1994)].In this regard, owing to the oxidative deaminization generation NH of MAO to the one-level monoamine
3, aldehyde and H
2O
2, be material, so this shows with selectivity MAO-B inhibitor for treating dementia and Parkinson's disease to have theoretical foundation with fixed or genotoxic potential.Suppress MAO-B and cause the enzyme deactivation of Dopamine HCL to reduce, thereby the validity of the neurotransmitter in the dopaminergic neuron is prolonged.Also be attributable to because the active H that increases and therefore cause of MAO with the denaturation process old and feeble, that alzheimer's disease is relevant with Parkinson's disease by MAO-B
2O
2Forming increases the oxidative stress that is caused.Therefore, the monoamine level plays a role in formation that the MAO-B inhibitor can be by reducing oxyradical and the rising brain.
Consider in above-mentioned neurological conditions to relate to MAO-B that people pay special attention to the effective and selective depressant that obtains this enzymic activity of may command.The pharmacology of some known MAO-B inhibitor is for example by discussion in CNS Drugs 6:217-236 (1996) such as Bentu é-Ferrer.A major limitation of non-reversibility and non-selective MAO inhibitor activity is to need to observe the eating attention item, because when absorption eats tyrasamine, exist and bring out danger and the existence and the interactional possibility [Gardner etc. of other medicines of hypertensive crisis, J.Clin.Psychiatry 57:99-104 (1996)], and less reversibility and the selective depressant with MAO, particularly MAO-B of these adverse events is relevant.Therefore, need have highly selective and not have the low optionally MAO-B inhibitor of the typical adverse side effect of non-reversibility MAO inhibitor this enzyme.
Found that formula I compound of the present invention and their pharmacologically acceptable salt are potential highly selective MAO-B inhibitor.In addition, theme of the present invention also have the method for preparation I compound, based on the medicine of compound of the present invention and their preparation method and these compounds in control or prevention by the purposes in the disease of monoamine oxidase B inhibitors mediation and these compounds purposes in the preparation relative medicine respectively.
No matter described term is to occur separately or make up appearance, and used generic term all is suitable for to give a definition in the present patent application.Must be pointed out: unless spell out in the context, used singulative also comprises plural form in specification sheets and the claims.
Used term " C among the application
1-C
6-alkyl " (" low alkyl group ") expression contains 1 to 6 carbon atom, preferably contains the straight or branched saturated hydrocarbyl of 1 to 4 carbon atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl etc.
Term " halogen " expression fluorine, chlorine, bromine and iodine.
" halogen-(C
1-C
6)-alkyl " mean on any position by the defined herein low alkyl group of one or more defined herein halogen atoms replacements.The example of halogen alkyl includes but not limited to 1,2-two fluoropropyls, 1,2-two chloropropyls, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls and 1,1,1-trifluoro propyl etc.
" C
1-C
6-alkoxyl group " mean residue-O-R, wherein R is defined low alkyl group herein.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, isopropoxy etc.
" the pharmaceutically useful salt " of compound means pharmacologically acceptable salts, they safe usually, nontoxic and biologically or others suit the requirements, and have the pharmacological activity of required parent compound.These salt are derived from inorganic or organic acid or alkali.Should be understood that all include the solvent addition form (solvate) or the crystalline form (polymorphic form) of this acid salt to referring to of pharmacologically acceptable salt.
In one embodiment, the invention provides wherein R
1For-(CH
2)
n-CO-NH
2And n is 0 or 1 formula I compound.
In one embodiment, the invention provides wherein R
1For-(CH
2)
n-COOR
7, R wherein
7Be hydrogen or C
1-C
6-alkyl and n are 0,1 or 2 formula I compound.In another embodiment, the invention provides wherein R
1For-(CH
2)
n-COOR
7, R wherein
7Be C
1-C
6-alkyl and n are 0 formula I compound.
In one embodiment, the invention provides wherein R
1For-(CH
2)
n-NH
2And n is 1 or 2 formula I compound.
In one embodiment, the invention provides wherein R
1For-(CH
2)
n-CN and n are 0,1 or 2 formula I compound.In another embodiment, the invention provides wherein R
1Formula I compound for-CN.
In one embodiment, the invention provides wherein R
1Formula I compound for the phenyl that replaced by halogen.
In one embodiment, the invention provides wherein R
2Be hydrogen or C
1-C
6The formula I compound of-alkyl.In another embodiment, the invention provides wherein R
2Formula I compound for hydrogen or methyl.
In one embodiment, the invention provides wherein R
3Be C
1-C
6-alkyl, C
3-C
6The formula I compound of-cycloalkyl or benzyl.In another embodiment, the invention provides wherein R
3Be C
3-C
6The formula I compound of-cycloalkyl.In another embodiment, the invention provides wherein R
3Formula I compound for benzyl.
In one embodiment, the invention provides wherein R
4It for halogen and m 1 formula I compound.
In compound of the present invention, preferred some formula I compound or pharmaceutically acceptable salt thereof.
Preferred formula I compound is R wherein
3Be those of hydrogen.
Preferred R wherein also
3Be (C
1-C
6The formula I compound of)-alkyl.Particularly preferably be wherein R
3Be those of methyl.
R wherein
3Be C
3-C
6The formula I compound of-cycloalkyl or benzyl also is preferred.
Preferred formula I compound also has wherein R
1For-(CH
2)
n-CO-NR
5R
6, R wherein
5And R
6Be hydrogen or C independently of one another
1-C
6Alkyl and n are those of 0,1 or 2.Particularly preferably be wherein R
5And R
6For hydrogen and n those compounds of 0,1 or 2.
Even R wherein more preferably
1For-(CH
2)
n-CO-NR
5R
6, R wherein
5And R
6It for hydrogen and n 0 formula I compound.
Following compound is the example:
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide,
2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethanamide and
2-[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide.
Preferred R wherein also
1For-(CH
2)
n-OR
8, R wherein
8Be hydrogen or C
1-C
6Alkyl and n are 0,1 or 2 formula I compound.Particularly preferably be wherein R
8For methyl and n those compounds of 1.
Following compound is the example:
7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one,
7-(4-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one and
7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-2-methyl-3H-quinazoline-4-one.
Preferred R wherein also
1For-(CH
2)
n-CO-NR
5R
6, R wherein
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl and n are 0,1 or 2 formula I compound.In this group compound, particularly preferably be wherein R
5And R
6For hydrogen and n be 0,1 or 2 those.
Following compound is the example:
3-(2-amino-ethyl)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one,
3-(3-amino-propyl group)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one,
1: 1 hydrochloride of 3-(2-amino-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one and
2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethyl-ammonium chloride.
Preferred formula I compound is R wherein particularly
4Be halogen or fluoro (C
1-C
6Those of)-alkyl.More preferably R
4Be fluorine.
In another embodiment, the invention provides and be selected from following formula I compound:
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide,
2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one,
7-(4-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one,
7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-2-methyl-3H-quinazoline-4-one,
3-(2-amino-ethyl)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one,
3-(3-amino-propyl group)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one,
1: 1 hydrochloride of 3-(2-amino-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one and
2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethyl-ammonium chloride.
On the other hand, the invention provides the method for preparation I compound and pharmacologically acceptable salt thereof, this method comprises makes formula IV compound:
Wherein:
R
3Be hydrogen, C
1-C
6-alkyl, C
3-C
6-cycloalkyl or benzyl;
R
4Be halogen, fluoro (C
1-C
6)-alkyl, cyano group, C
1-C
6-alkoxyl group or fluoro (C
1-C
6)-alkoxyl group; And
M is 1,2 or 3
React with formula V compound:
Wherein:
R
1For-(CH
2)
n-CO-NR
5R
6-(CH
2)
n-COOR
7-(CH
2)
n-NR
5R
6-(CH
2)
n-CN;-(CH
2)
n-OR
8Or phenyl, it is for unsubstituted or be selected from halogen and fluoro (C by 1 to 3
1-C
6The substituting group of)-alkyl replaces;
R
2Be hydrogen, halogen or C
1-C
6-alkyl;
R
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl;
R
7Be hydrogen or C
1-C
6-alkyl;
R
8Be hydrogen or C
1-C
6-alkyl; And
N is 0,1 or 2;
And randomly the formula I compound of gained is converted into pharmacologically acceptable salt.
In one embodiment, the compound of general formula I and their pharmacologically acceptable salt can prepare by the following method: make formula II compound:
R wherein
3Be hydrogen,
React with the formula III compound:
To obtain formula IV compound:
R wherein
3Be hydrogen,
Make the reaction of formula IV compound and formula V compound then:
With acquisition formula I compound,
And if desired, formula I compound is converted into pharmacologically acceptable salt,
Perhaps,
Make formula VI compound:
React with formula VII compound:
To obtain formula IV compound, make formula IV compound and formula V reaction with acquisition formula I compound then, and if desired, formula I compound is converted into pharmacologically acceptable salt.
According to the present invention, the compound of general formula I can prepare according to following schema 1: there is heating down in 2-amino-4-fluorobenzoic acid VIII in acetate carbonamidine IX, obtains IIa type compound after the reaction medium alkalization.Sodium salt with X type benzylalcohol reacts then, obtains IVa type compound, then this compound dissolution is handled in 1-Methyl-2-Pyrrolidone (NMP) and with the electrophilic reagent of sodium hydride and formula V, obtains formula I compound, wherein R
3Be hydrogen.
Schema 1
Perhaps, the compound of general formula I can be according to following schema 2 preparation: there is heating down in 4-fluoro-2-nitro-benzonitrile XI and with the sour XII acidic methanol esterification of gained, obtains the compound of formula XIII in HBr.Sodium salt with X type benzylalcohol reacts then, obtains XIV type compound, is the aniline of formula VI then with this hydrogenation of compounds.In alkali (being generally sodium methylate), handle, form quinazolinone IV, use the V-type compound then, form the target compound of formula I its alkylation with VII type ethanimidic acid ester hydrochloride.
Schema 2
According to known method itself and consider the character of the compound for salt to be transformed, the pharmacologically acceptable salt of preparation I compound easily.Mineral acid or organic acid are suitable for forming the pharmacologically acceptable salt of alkaline formula I compound as for example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, toxilic acid, acetate, succsinic acid, tartrate, methylsulfonic acid, tosic acid etc.Alkali metal containing or alkaline-earth metal for example compound, basic amine or the basic aminoacids of sodium, potassium, calcium, magnesium etc. are suitable for forming the pharmacologically acceptable salt of acidic cpd.
Mentioned that as above formula I compound and its pharmacologically acceptable salt are monoamine oxidase B inhibitors, can be used for treating or prevent the MAO-B inhibitor to its may be useful disease.These diseases comprise acute and chronic neurological illness, cognitive disorder and memory impairment.Medicable neurological conditions has for example neural traumatic or chronic denaturation process, as the dementia of alzheimer's disease, other type, slight cognitive impairment (minimal cognitive impairment) or Parkinson's disease.Other indication comprises mental disorder such as dysthymia disorders, anxiety disorder, panic attack, social phobia, schizophrenia, feed and metabolic disturbance such as obesity, and prevents and treat the withdrawal symptom that abuse of alcohol, Nicotine and other addictive drug bring out.Other medicable indication can be peripheral neurophaty (WO 97/33572) or treatment multiple sclerosis (WO 96/40095) and other the neural inflammatory diseases that award shortage syndrome (reward deficiency syndrome) (WO 01/34172), cancer chemotherapy cause.
Checked the pharmacological activity of described compound in order to following method: use Schlaeger and Christensen[Cytotechnology, 15:1-13 (1998)] described method, with the cDNA transient transfection of coding people MAO-A and MAO-B in the EBNA cell.After the transfection, cell is carried out homogenizing with the Polytron homogenizer in the 20mMTris HCl damping fluid of the pH 8.0 that contains 0.5mM EGTA and 0.5mM phenyl methanesulfonamide acyl fluorides.By the centrifugal cytolemma that obtains under 45,000 * g, after the 20mM Tris HCl damping fluid washed twice with the pH 8.0 that contains 0.5mM EGTA, at last cytolemma is suspended in the above-mentioned damping fluid again, and standby under aliquots containig being stored in-80 ℃.
Use is by Zhou and Panchuk-Voloshina[Analytical Biochemistry, 253:169-174 (1997)] spectrophotometry that obtains of described method improvement measures the enzymic activity of MAO-A and MAO-B on 96 orifice plates.In brief, with the aliquots containig of film in the 0.1M of pH7.4 potassium phosphate buffer in 37 ℃ of following incubations 30 minutes, have or do not exist the compound of various concentration.Afterwards, by adding horseradish peroxidase (RocheBiochemicals) and the 80 μ M N-ethanoyl-3 of MAO substrate tyrasamine and 1U/ml, the reaction of 7-dihydroxyl phenoxazine (Amplex Red, Molecular Probes) primase.Sample with the final volume of 200 μ l incubation 30 minutes again under 37 ℃, is used SpectraMax to read plate instrument (Molecular Devices) then and measure optical density under the 570nm wavelength.In the presence of the L-SelegilineHydrochloride of 10 μ M, measuring background (non-specific) absorption for MAO-A in the presence of the M and B 9302 of 10 μ M or for MAO-B.Determine IC by being four parameter logarithmic equations with data fitting by the inhibition curve that obtains with bipartite 9 inhibitor concentration with computer program
50Value.
Compound of the present invention is a specificity MAO-B inhibitor.The activity of the formula I compound that records in the said determination method is 10 μ M or littler, is generally 1 μ M or littler, is desirably 0.3 μ M or littler.
Formula I compound and their pharmacologically acceptable salt useful as drug for example are used as medicine with the medicinal preparations form.Described pharmaceutical preparation can be Orally administered, for example with tablet, coated tablet, dragee, hard and Gelseal, solution, emulsion or suspensoid form are Orally administered.But, also can use by per rectum, for example use, or use through parenteral with the suppository form per rectum, for example use through parenteral with injection solution agent form.
Can with the pharmacologically acceptable salt of formula I compound and they with the pharmacy inert inorganic or organic carrier process with useful in preparing drug formulations.Lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc. can be used as for example carrier of tablet, coated tablet, dragee and hard-gelatin capsules.The appropriate carrier that is used for Gelseal is for example vegetables oil, wax, fat, semisolid and liquid polyol etc.; But depending on the character of active substance for Gelseal, does not need carrier usually.The appropriate carrier that is used to prepare solution and syrup has for example water, polyvalent alcohol, sucrose, Nulomoline, glucose etc.Assistant agent can be used for the water-based injection solution agent of the water-soluble salt of formula I compound as alcohol, polyvalent alcohol, glycerine, plant wet goods, but optional usually.The appropriate carrier that is used for suppository has for example natural or winterized stearin, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical preparation can comprise salt, buffer reagent, sequestering agent or the antioxidant of sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, correctives, adjusting osmotic pressure.They can also comprise other treatment and go up valuable material.
As mentioned above, comprising formula I compound or pharmaceutically acceptable salt thereof and treating the medicine of going up inert excipients also is purpose of the present invention, purpose of the present invention also comprises the method for preparing described medicine, this method comprises makes one or more formulas I compound or pharmaceutically acceptable salt thereof and if desired, and one or more other treatment is gone up valuable material and gone up inert carrier formation galenical with one or more treatments.
Dosage can change in wide limit, and will meet the individual demand in each case-specific certainly.Generally speaking, being used for effective dose oral or that parenteral is used is 0.01-20mg/kg/ days, and preferred dosage is 0.1-10mg/kg/ days, is applicable to all described indications.For the grownup of body weight 70kg, per daily dose correspondingly is 0.7-1400mg every day, and preferred every day 7 is to 700mg.
Provide following examples to illustrate the present invention.They should not be considered to limitation of the scope of the invention, and only are representatives of the present invention.Term " room temperature " is abbreviated as " rt ".
Embodiment 1:2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide
A) 7-fluoro-3H-quinazoline-4-one: (14.6g, 94mmol) (19.6g, 18.8mmol) mixture in 2-methyl cellosolve (110ml) heated 18 hours down at 130 ℃ with the acetate carbonamidine with 2-amino-4-fluoro-phenylformic acid.After the cooling, mixture is evaporated half, form pale solid.Mixture with ammonia (25%, 10ml is in 90ml water) dilution, is leached solid and washes with water.Then with solid with hexane wash and dry under high vacuum, obtain title compound (12.5g, 81%), be pale solid.MS：m/e＝165.2(M+H
+)。
B) 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one: (1.8g is 78.6mmo1) by heating 4 hours in 80-90 ℃ under argon gas in part adding 3-fluoro benzyl alcohol and with the gained mixture with sodium.The gained suspension is cooled to room temperature, adds 7-fluoro-3H-quinazoline-4-one (3.2g, 19.5 mmol) and the gained mixture is descended heating 14 hours at 130-140 ℃.With solid water (400ml) dissolving of formation and with HCl (4N) mixture is acidified to pH 3-4 then.Leach throw out and the water (100ml) and ether (100ml) washing of generation then.Use tetrahydrofuran (THF): ethyl acetate (1: 1) recrystallization, obtain title compound (3.2g, 61%), be white crystal.MS：m/e＝271.3(M+H
+)。
C) 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3 base]-ethanamide: with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one (200mg, 0.74mmol) and sodium hydride (55%, 36mg, 0.81mmol) mixture in N-Methyl pyrrolidone (5ml) is 60 ℃ of down heating 1 hour.(117mg 0.85mmol) and with the gained mixture heated 1 hour down at 80 ℃ to add bromoacetamide then.After being cooled to room temperature, adding entry (50ml) and use methyl alcohol and ether to wash the gained throw out, dry under high vacuum then, obtain title compound (200mg, 83%), be pale solid.MS：m/e＝328.3(M+H
+)。
Embodiment 2:2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (190mg, 75%) (using 2-bromine propionic acid amide to replace bromoacetamide), and the title compound that obtains is a white solid with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one.MS：m/e＝342.3(M+H
+)。
Embodiment 3:7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one
Described in embodiment 1c, with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one (200mg, 0.74mmol) be converted into title compound (165mg, 68%) [using (2-brooethyl) methyl ether to replace bromoacetamide], use ether: the title compound that obtains after the heptane crystallization is a white solid.MS：m/e＝342.3(M+H
+)。
Embodiment 4:3-(2-amino-ethyl)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one
A) 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl }-t-butyl carbamate: described in embodiment 1c, with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one (200mg, 0.74mmol) be converted into title compound (175mg, 57%) [use 2-(Boc-amino) monobromoethane to replace bromoacetamide], use ether: the title compound that obtains after the heptane crystallization is a white solid.MS：m/e＝342.3(M+H
+)。
B) 3-(2-amino-ethyl)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one: will 2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl }-(150mg, 0.36mmol) (4N, 3ml) mixture in at room temperature stirred 72 hours t-butyl carbamate with HCl Zai diox.Leach throw out and, obtain title compound (120mg, 86%), be white solid with the ether washing.MS：m/e＝314.3(M+H
+)。
Embodiment 5:[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl acetate
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (170mg, 65%) [using ethyl bromoacetate to replace bromoacetamide], and the title compound that obtains is a white solid with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one.MS：m/e＝357.3(M+H
+)。
Embodiment 6: fluoro-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl acetate
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (100mg, 36%) [using ethyl bromide fluoride to replace bromoacetamide], by chromatography (SiO with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, CH
2Cl
2: 2N NH
3/ MeOH 99: 1 to 9: 1) and use ether: the title compound that the heptane crystallization carries out obtaining behind the purifying is a white solid.MS：m/e＝375.4(M+H
+)。
Embodiment 7:2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl propionate
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (240mg, 88%) [using 2-bromo-ethyl propionate to replace bromoacetamide], by chromatography (SiO with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, CH
2Cl
2: 2N NH
3/ MeOH 99: 1 to 9: 1) title compound that obtains behind the purifying is a colorless oil.MS：m/e＝371.3(M+H
+)。
Embodiment 8:[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-tert.-butyl acetate
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (277mg, 97%) [using bromo-acetic acid tert-butyl to replace bromoacetamide], by chromatography (SiO with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, CH
2Cl
2: 2N NH
3/ MeOH 99: 1 to 9: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝385.3(M+H
+)。
Embodiment 9:2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-the propionic acid tert-butyl ester
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (245mg, 83%) [using the 2 bromopropionic acid tert-butyl ester to replace bromoacetamide], by chromatography (SiO with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, CH
2Cl
2: 2N NH
3/ MeOH 99: 1 to 9: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝385.3(M+H
+)。
Embodiment 10:3-(3-amino-propyl group)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one
A) 3-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propyl group }-t-butyl carbamate: as
Described in the embodiment 1c, (200mg 0.74mmol) is converted into title compound (312mg, 99%) [using 3-(Boc-amino) propyl bromide to replace bromoacetamide], by chromatography (SiO with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, CH
2Cl
2: 2N NH
3/ MeOH 99: 1 to 9: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝428.5(M+H
+)。
B) 3-(3-amino-propyl group)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one: will 3-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propyl group }-(275mg, 0.64mmol) (4N, 8ml) mixture in at room temperature stirred 16 hours t-butyl carbamate with HCl Zai diox.Leach throw out and use EtOH: the ether recrystallization, obtain title compound (120mg, 47%), be white solid.MS：m/e＝328.3(M+H
+)。
Embodiment 11:3-(3-fluoro-benzyl)-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
Described in embodiment 1c, (200mg 0.74mmol) is converted into title compound (253mg, 90%) [using the 3-fluoro benzyl bromide to replace bromoacetamide], by chromatography (SiO with 7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, CH
2Cl
2: 2N NH
3/ MeOH 99: 1 to 9: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝379.3(M+H
+)。
Embodiment 12:2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide
A) 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one: with sodium hydride (55%, 3.2g, 73mmol), the 4-fluoro benzyl alcohol (9.2g, 73mmol) and 7-fluoro-3H-quinazoline-4-one (3.0g, 18mmol) mixture in DMF (75ml) is 140 ℃ of down heating 2 hours.The gained suspension is cooled to room temperature, mixture is acidified to pH3 with HCl (dense).Leach the throw out of generation, water and ether washing.By the silica gel chromatography partial purification, use ethyl acetate: hexane (2: 1) wash-out, obtain title compound (3.2g, 66%), be pale solid.MS：m/e＝271.3(M+H
+)。
B) 2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide: described in embodiment 1c, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (embodiment 12a, 200mg, 0.74mmol) be converted into title compound (20mg, 8%), (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝328.3(M+H
+)。
Embodiment 13:2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide
Described in embodiment 1c, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (400mg, 1.5mmol) be converted into title compound (37mg, 7%) [use 2-bromine propionic acid amide to replace bromoacetamide], (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝340.2(M+H
+)。
Embodiment 14:[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl acetate
Described in embodiment 1c, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (400mg, 1.5mmol) be converted into title compound (83mg, 16%) [use ethyl bromoacetate to replace bromoacetamide], (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝357.3(M+H
+)。
Embodiment 15:2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl propionate
Described in embodiment 1c, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (400mg, 1.5mmol) be converted into title compound (32mg, 6%) [use the 2 bromopropionic acid ethyl ester to replace bromoacetamide], (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝371.3(M+H
+)。
Embodiment 16:7-(4-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one
As described in example 3 above, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (400mg, 1.5mmol) be converted into title compound (115mg, 24%), (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝329.1(M+H
+)。
Embodiment 17:3-(2-amino-ethyl)-7-(4-fluoro-benzyloxy)-1: 1 hydrochloride of 3H-quinazoline-4-one
A) 2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl }-t-butyl carbamateAs
Described in the embodiment 10a, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (300mg, 1.1mmol) be converted into title compound (105mg, 23%), (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝414.5(M+H
+)。
B) 3-(2-amino-ethyl)-7-(4-fluoro-benzyloxy)-1: 1 hydrochloride of 3H-quinazoline-4-one: described in embodiment 10b, will 2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethyl }-t-butyl carbamate (102mg, 0.25mmol) being converted into title compound (84mg, 97%), the title compound that obtains is a white solid.MS：m/e＝314.2(M+H
+)。
Embodiment 18:3-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide
Described in embodiment 1c, with 7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one (300mg, 1.1mmol) be converted into title compound (72mg, 19%) [use 3-bromine propionic acid amide to replace bromoacetamide], (title compound that obtains behind Waters Xterra RP18 (5 μ m * 50 * the 19mm)) purifying is a white solid by the HPLC with the AcCN/0.1%TFA/ water elution.MS：m/e＝342.1(M+H
+)。
Embodiment 19:2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethanamide
A) 4-fluoro-2-nitro-phenylformic acid: with 4-fluoro-2-nitro-benzonitrile (12.2g, 73.7mmol) be suspended in HBr (48%, 74.5ml, 664mmol) mixture in heated 6.5 hours under 130 ℃ of C.After being cooled to room temperature, adding entry (1L) and, obtain title compound (11.0g, 81%), be the light brown solid the throw out water and the hexane wash of gained.MS：m/e＝183.9(M-H)。
B) 4-fluoro-2-nitro-methyl benzoate: (1.8g, (10.9g, 58.8mmol) mixture in methyl alcohol (120ml) heated 41 hours under refluxing 4-fluoro-2-nitro-phenylformic acid 18.7mmol) will to contain sulfuric acid.After being cooled to room temperature, with mixture impouring sodium bicarbonate (saturated, 250ml) in and with ethyl acetate (3 * 100ml) extraction.With the extraction liquid that merges salt solution (100ml) washing, dry and evaporation, obtain title compound (10.7g, 91%), be light brown liquid.MS：m/e＝199.0(M-H)。
C) 4-(3-fluoro-benzyloxy)-2-nitro-phenylformic acid (3-fluoro-benzyl) ester and 4-(3-fluoro-benzyloxy)-2-nitro- The benzene methyl methyl esters: with 4-fluoro-2-nitro-methyl benzoate (9.2g, 46.3mmol), the 3-fluoro benzyl alcohol (16.7g, 132.4mmol) and salt of wormwood (12.8g, 92.6mmol) mixture in DMF (210ml) is 65 ℃ of down heating 48 hours.After being cooled to room temperature, with (3 * 100ml) extract in the mixture impouring water (400ml) and with ether.With the extraction liquid that merges salt solution (100ml) washing, dry and evaporation.By the silica gel chromatography purifying, use ethyl acetate: hexane (1: 1) wash-out, obtain title compound (14.0g, 76%), be light yellow liquid.
D) 4-(3-fluoro-benzyloxy)-2-nitro-phenylformic acid: will contain lithium hydroxide monohydrate (2.94g, 70.1mmol) 4-(3-fluoro-benzyloxy)-2-nitro-phenylformic acid (3-fluoro-benzyl) ester and 4-(3-fluoro-benzyloxy)-2-nitro-methyl benzoate (14.0g, 35.0mmol) mixture in THF (120ml) and water (120ml) at room temperature stirred 48 hours.Then with mixture impouring sodium hydroxide (2N, 50ml) in and (3 * 150ml) extract this mixture with ether.Then water is transferred to pH2 with HCl.Then with mixture impouring sodium hydroxide (2N, 50ml) in and water transferred to pH5.2 with HCl, use ether (3 * 100ml) extraction mixtures then.With the extraction liquid that merges salt solution (100ml) washing, dry and evaporation, obtain title compound (6.6g, 65%) then, be light yellow solid.MS：m/e＝290.0(M-H)。
E) 2-amino-4-(3-fluoro-benzyloxy)-phenylformic acid: with 4-(3-fluoro-benzyloxy)-2-nitro-phenylformic acid (7.2g, 24.8mmol) mixture in ethyl acetate (150ml) in Pt/C (5%, 1.0g) exist down, hydrogenation 3.5 hours under room temperature and pressure.Then mixture is filtered and evaporated filtrate.Grind gained light brown solid with methylene dichloride (DCM), obtain title compound (5.2g, 80%), be pale solid.MS：m/e＝260.1(M-H)。
Perhaps, with 4-(3-fluoro-benzyloxy)-2-nitro-phenylformic acid (6.6g, 22.8mmol) mixture in ethyl acetate (140ml) in Pd/C (5%, 1.0g) exist down, hydrogenation 3.5 hours under room temperature and pressure.Then mixture is filtered and evaporated filtrate.Grind gained light brown solid with DCM, obtain title compound (5.1g, 87%), be pale solid.
F) 7-(3-fluoro-benzyloxy)-2-methyl-3H-quinazoline-4-one: to 2-amino-4-(3-fluoro-benzyloxy)-phenylformic acid (2.0g, 7.7mmol) and ethanimidic acid ethyl ester HCl (1.9g, 15.3mmol) (5.4M, 0.83g is 15.3mmol) and with the heating 19 hours under refluxing of gained mixture to add sodium methylate in the mixture in methyl alcohol (30ml).After this add ethanimidic acid ethyl ester HCl (1.9g, 15.3mmol) and sodium methylate (5.4M, 0.83g is 15.3mmol) and with gained mixture reheat 1 hour.After being cooled to room temperature, in mixture impouring water (40ml), then the gained throw out is stirred 2 hours, leach, obtain title compound (2.1g, 97%), be pale solid.MS：m/e＝283.1(M-H)。
G) 2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethanamide: described in embodiment 1c, (250mg 0.88mmol) is converted into title compound (218mg, 73%), and the title compound that obtains after grinding with methylene dichloride (DCM) is a white solid with 7-(3-fluoro-benzyloxy)-2-methyl-3H-quinazoline-4-one.MS：m/e＝342.1(M+H
+)。
Embodiment 20:7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-2-methyl-3H-quinazoline-4-one
As described in example 3 above, (250mg 0.88mmol) is converted into title compound (150mg, 45%), by chromatography (SiO with 7-(3-fluoro-benzyloxy)-2-methyl-3H-quinazoline-4-one
2, EtOAc: heptane 1: 3 to 2: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝343.1(M+H
+)。
Embodiment 21:2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethyl-ammonium chloride
A) 2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethyl }-the carboxylamine uncle Butyl ester: described in embodiment 4a, (250mg 0.88mmol) is converted into title compound (72mg, 18%), by chromatography (SiO with 7-(3-fluoro-benzyloxy)-2-methyl-3H-quinazoline-4-one
2, EtOAc: heptane 1: 4 to 2: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝428.3(M+H
+)。
B) 2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethyl-ammonium chloride: described in embodiment 4b, will 2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-] ethyl-(50mg 0.12mmol) is converted into title compound (45mg, 85%) to t-butyl carbamate, by chromatography (SiO
2, EtOAc: heptane 1: 4 to 2: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝328.2(M+H
+)。
Embodiment 22:2-[7-(3-fluoro-benzyloxy)-2-sec.-propyl-4-oxo-4H-quinazoline-3-yl]-ethanamide
A) 7-(3-fluoro-benzyloxy)-2-sec.-propyl-3H-quinazoline-4-one: described in embodiment 19f, (1g 3.8mmol) is converted into title compound (196mg, 16%) [using sec.-propyl imidic acid ethyl ester HCl to replace ethanimidic acid ethyl ester HCl], by chromatography (SiO with 2-amino-4-(3-fluoro-benzyloxy)-phenylformic acid
2, methylene dichloride: MeOH 95: 5 to 85: 15) and the title compound that obtains behind the purifying is white solid.MS：m/e＝330.1(M+NH
4 +)。
B) 2-[7-(3-fluoro-benzyloxy)-2-sec.-propyl-4-oxo-4H-quinazoline-3-yl]-ethanamide: described in embodiment 1c, (80mg 0.26mmol) is converted into title compound (84mg, 89%), and the title compound that obtains after grinding with methylene dichloride is a white solid with 7-(3-fluoro-benzyloxy)-2-sec.-propyl-3H-quinazoline-4-one.MS：m/e＝370.2(M+H
+)。
Embodiment 23:[7-(3-fluoro-benzyloxy)-2-sec.-propyl-4-oxo-4H-quinazoline-3-yl]-acetonitrile
To 2-[7-(3-fluoro-benzyloxy)-2-sec.-propyl-4-oxo-4H-quinazoline-3-yl]-ethanamide (50mg, 0.14mmol) add N-ethyl-N in the mixture in dimethyl formamide (0.5ml), methylene dichloride (2ml), (26.2mg 0.2mmol) and with the gained mixture is cooled to-78 ℃ to the N-diisopropylamine.(49.6mg 0.18mmol) and in 30 minutes is warming up to room temperature with reaction mixture to add trifluoromethanesulfanhydride anhydride then.Then with gained mixture impouring sodium bicarbonate (saturated, 5ml) in and with ether (3 * 5ml) extraction mixtures.Then the extraction liquid that merges is also evaporated with salt water washing, drying, obtain light yellow solid.By chromatography (SiO
2, EtOAc: purifying heptane 1: 1 to 85: 15), obtain title compound (26mg, 55%), be white solid.MS：m/e＝352.2(M+H
+)。
Embodiment 24:2-[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide
A) 2-cyclopropyl-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one: described in embodiment 19f, with 2-amino-4-(3-fluoro-benzyloxy)-phenylformic acid (1.0g, 3.8mmol) be converted into title compound (607mg, 49%) [use cyclopropyl imidic acid ethyl ester HCl to replace ethanimidic acid ethyl ester HCl], the title compound that obtains after grinding with ether is a white solid.MS：m/e＝311.2(M+H
+)。
B) 2-[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide: described in embodiment 1c, (80mg 0.26mmol) is converted into title compound (98mg, 65%), by chromatography (SiO with 2-cyclopropyl-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, methylene dichloride: MeOH 98: 2 to 9: 1) and the title compound that obtains behind the purifying is white solid.MS：m/e＝368.1(M+H
+)。
Embodiment 25:2-cyclopropyl-7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one
As described in example 3 above, (150mg 0.48mmol) is converted into title compound (15mg, 8%), by chromatography (SiO with 2-cyclopropyl-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, methylene dichloride: MeOH 95: 5) and the title compound that obtains behind the purifying is white solid.MS：m/e＝369.2(M+H
+)。
Embodiment 26:[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-methyl acetate
Described in embodiment 1c, (100mg 0.3mmol) is converted into title compound (33 mg, 27%) [using methyl bromoacetate to replace bromoacetamide], by chromatography (SiO with 2-cyclopropyl-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, EtOAc: heptane 1: 9 to 1: 1) title compound that obtains behind the purifying is a white solid.MS：m/e＝383.3(M+H
+)。
Embodiment 27:2-[2-benzyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide
A) 2-benzyl-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one: described in embodiment 19f, with 2-amino-4-(3-fluoro-benzyloxy)-phenylformic acid (1.0g, 3.8mmol) being converted into title compound (731mg, 53%) [using benzyl imidic acid ethyl ester HCl to replace ethanimidic acid ethyl ester HCl], the title compound that obtains after grinding with ether is a white solid.MS：m/e＝361.2(M+H
+)。
B) 2-[2-benzyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide: described in embodiment 1c, (150mg 0.42mmol) is converted into title compound (94mg, 54%), by chromatography (SiO with 2-benzyl-7-(3-fluoro-benzyloxy)-3H-quinazoline-4-one
2, methylene dichloride: MeOH 99: 1 to 9: 1) and the title compound that obtains behind the purifying is white solid.MS：m/e＝418.2(M+H
+)。
Embodiment A: tablet
The tablet that has following composition by the ordinary method preparation:
The mg/ sheet
Activeconstituents 100
Powdery lactose 95
White cornstarch 35
Polyvinylpyrrolidone 8
Sodium starch glycolate 10
Magnesium Stearate 2
Sheet is heavy
250
Embodiment B: tablet
The tablet that has following composition by the ordinary method preparation:
The mg/ sheet
Activeconstituents 200
Powdery lactose 100
White cornstarch 64
Polyvinylpyrrolidone 12
Sodium starch glycolate 20
Magnesium Stearate 4
Sheet is heavy
400
Embodiment C: capsule
Preparation has the capsule of following composition:
The mg/ capsule
Activeconstituents 50
Crystallization lactose 60
Microcrystalline Cellulose 34
Talcum powder 5
Magnesium Stearate 1
The capsule filling weight
150
Activeconstituents, crystallization lactose and the Microcrystalline Cellulose that will have suitable granularity are mixed with each other evenly, sieve, and are mixed into talcum powder and Magnesium Stearate then.Whole mixture is packed in the hard gelatin capsule of suitable size.
Embodiment D: injection liquid
Injection liquid can have following composition and prepare with ordinary method:
Active substance 1.0mg
1N?HCl 20.0μl
Acetate 0.5mg
NaCl 8.0mg
Phenol 10.0mg
1N NaOH adds to pH5 in right amount
H
2O adds to 1ml in right amount
Claims (11)
1. formula I compound:
Wherein:
R
1For-(CH
2)
n-CO-NR
5R
6-(CH
2)
n-COOR
7-(CH
2)
n-NR
5R
6-(CH
2)
n-CN;-(CH
2)
n-OR
8Or phenyl, it is for unsubstituted or be selected from halogen and fluoro (C by 1 to 3
1-C
6The substituting group of)-alkyl replaces;
R
2Be hydrogen, halogen or C
1-C
6-alkyl;
R
3Be hydrogen, C
1-C
6-alkyl, C
3-C
6-cycloalkyl or benzyl;
R
4Be halogen, fluoro (C
1-C
6)-alkyl, cyano group, C
1-C
6-alkoxyl group or fluoro (C
1-C
6)-alkoxyl group;
R
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl;
R
7Be hydrogen or C
1-C
6-alkyl;
R
8Be hydrogen or C
1-C
6-alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
And their pharmacologically acceptable salt.
2. the formula I compound of claim 1, wherein:
R
1For-(CH
2)
n-CO-NR
5R
6-(CH
2)
n-COOR
7-(CH
2)
n-NR
5R
6-(CH
2)
n-CN;-(CH
2)
n-OR
8Or phenyl, it is for unsubstituted or be selected from halogen and fluoro (C by 1 to 3
1-C
6The substituting group of)-alkyl replaces;
R
2Be hydrogen or C
1-C
6-alkyl;
R
3Be hydrogen, C
1-C
6-alkyl, C
3-C
6-cycloalkyl or benzyl;
R
4Be halogen, fluoro (C
1-C
6)-alkyl, cyano group, C
1-C
6-alkoxyl group or fluoro (C
1-C
6)-alkoxyl group;
R
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl;
R
7Be hydrogen or C
1-C
6-alkyl;
R
8Be hydrogen or C
1-C
6-alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
And their pharmacologically acceptable salt.
3. the formula I compound of claim 1, it is selected from:
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[7-(4-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-propionic acid amide,
2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethanamide,
2-[2-cyclopropyl-7-(3-fluoro-benzyloxy)-4-oxo-4H-quinazoline-3-yl]-ethanamide,
7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one,
7-(4-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-3H-quinazoline-4-one,
7-(3-fluoro-benzyloxy)-3-(2-methoxyl group-ethyl)-2-methyl-3H-quinazoline-4-one,
3-(2-amino-ethyl)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one,
3-(3-amino-propyl group)-7-(3-fluoro-benzyloxy)-1: 2 hydrochloride of 3H-quinazoline-4-one,
1: 1 hydrochloride of 3-(2-amino-ethyl)-7-(4-fluoro-benzyloxy)-3H-quinazoline-4-one and
2-[7-(3-fluoro-benzyloxy)-2-methyl-4-oxo-4H-quinazoline-3-yl]-ethyl-ammonium chloride.
4. prepare the formula I compound of claim 1 and the method for pharmacologically acceptable salt thereof, this method comprises: make formula IV compound:
Wherein:
R
3Be hydrogen, C
1-C
6-alkyl, C
3-C
6-cycloalkyl or benzyl;
R
4Be halogen, fluoro (C
1-C
6)-alkyl, cyano group, C
1-C
6-alkoxyl group or fluoro (C
1-C
6)-alkoxyl group; And
M is 1,2 or 3
React with formula V compound:
Wherein:
R
1For-(CH
2)
n-CO-NR
5R
6-(CH
2)
n-COOR
7-(CH
2)
n-NR
5R
6-(CH
2)
n-CN;-(CH
2)
n-OR
8Or phenyl, it is for unsubstituted or be selected from halogen and fluoro (C by 1 to 3
1-C
6The substituting group of)-alkyl replaces;
R
2Be hydrogen, halogen or C
1-C
6-alkyl;
R
5And R
6Be hydrogen or C independently of one another
1-C
6-alkyl;
R
7Be hydrogen or C
1-C
6-alkyl;
R
8Be hydrogen or C
1-C
6-alkyl; And
N is 0,1 or 2;
And randomly the formula I compound of gained is converted into pharmacologically acceptable salt.
5. be used for the treatment of and prevent the medicine of the disease of monoamine oxidase B inhibitors mediation, it contains the formula I compound or pharmaceutically acceptable salt thereof and the pharmaceutically useful vehicle of claim 1.
6. the medicine of claim 5, it is the medicine that is used for the treatment of and prevents alzheimer's disease and senile dementia.
7. with the formula I compound or pharmaceutically acceptable salt thereof of the claim 1 of the method for claim 4 preparation.
8. be used for the treatment of or the formula I compound and the pharmacologically acceptable salt thereof of prophylactic claim 1.
9. the formula I compound of claim 1 and pharmacologically acceptable salt thereof the purposes in the medicine of the disease of preparation treatment and the mediation of prevention monoamine oxidase B inhibitors.
10. the purposes of claim 9, wherein said disease is alzheimer's disease or senile dementia.
11. below described herein invention.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02027700.0 | 2002-12-13 | ||
| EP02027700 | 2002-12-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1720237A true CN1720237A (en) | 2006-01-11 |
| CN100418954C CN100418954C (en) | 2008-09-17 |
Family
ID=32524001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801052982A Expired - Fee Related CN100418954C (en) | 2002-12-13 | 2003-12-08 | 3h-quinazolin-4-one derivatives |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US7087612B2 (en) |
| EP (1) | EP1572666B1 (en) |
| JP (1) | JP4384053B2 (en) |
| KR (1) | KR100707532B1 (en) |
| CN (1) | CN100418954C (en) |
| AR (1) | AR042362A1 (en) |
| AT (1) | ATE335729T1 (en) |
| AU (1) | AU2003293798B8 (en) |
| BR (1) | BR0317282A (en) |
| CA (1) | CA2509633A1 (en) |
| CL (1) | CL2003002565A1 (en) |
| DE (1) | DE60307512T2 (en) |
| ES (1) | ES2270154T3 (en) |
| GT (1) | GT200300284A (en) |
| MX (1) | MXPA05006124A (en) |
| MY (1) | MY141743A (en) |
| PA (1) | PA8591901A1 (en) |
| PE (1) | PE20040911A1 (en) |
| PL (1) | PL377474A1 (en) |
| RU (1) | RU2340604C2 (en) |
| TW (1) | TW200424180A (en) |
| UY (1) | UY28120A1 (en) |
| WO (1) | WO2004054985A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191667A (en) * | 2018-01-04 | 2018-06-22 | 利尔化学股份有限公司 | The preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7846915B2 (en) | 2004-10-20 | 2010-12-07 | Resverlogix Corporation | Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases |
| KR20070094666A (en) | 2005-02-25 | 2007-09-20 | 에프. 호프만-라 로슈 아게 | Tablets with improved drug substance dispersibility |
| CA2617213C (en) | 2005-07-29 | 2014-01-28 | Resverlogix Corp. | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices |
| GB0525068D0 (en) * | 2005-12-08 | 2006-01-18 | Novartis Ag | Organic compounds |
| JP4876690B2 (en) * | 2006-04-21 | 2012-02-15 | 三菱瓦斯化学株式会社 | Method for producing quinazolin-4-one derivative |
| WO2008087736A1 (en) * | 2007-01-19 | 2008-07-24 | Ube Industries, Ltd. | Process for producing aromatic amine having aralkyloxy or heteroaralkyloxy group |
| US8053440B2 (en) | 2007-02-01 | 2011-11-08 | Resverlogix Corporation | Compounds for the prevention and treatment of cardiovascular diseases |
| PL2346837T3 (en) | 2008-06-26 | 2015-07-31 | Resverlogix Corp | Methods of preparing quinazolinone derivatives |
| ES2463097T3 (en) | 2009-01-08 | 2014-05-27 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular diseases |
| EP2408454A2 (en) | 2009-03-18 | 2012-01-25 | Resverlogix Corp. | Novel anti-inflammatory agents |
| NZ596117A (en) | 2009-04-22 | 2014-10-31 | Resverlogix Corp | Novel anti-inflammatory agents |
| ES2745471T3 (en) | 2011-11-01 | 2020-03-02 | Resverlogix Corp | Oral immediate-release formulations for substituted quinazolinones |
| US9765039B2 (en) | 2012-11-21 | 2017-09-19 | Zenith Epigenetics Ltd. | Biaryl derivatives as bromodomain inhibitors |
| WO2014080290A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Cyclic amines as bromodomain inhibitors |
| AU2013365926B9 (en) | 2012-12-21 | 2019-01-17 | Zenith Epigenetics Ltd. | Novel heterocyclic compounds as bromodomain inhibitors |
| CN114984016A (en) | 2015-03-13 | 2022-09-02 | 雷斯韦洛吉克斯公司 | Compositions and methods for treating complement-associated diseases |
| CN106146410B (en) * | 2015-04-03 | 2018-10-12 | 中南大学 | 6- amino -4 (3H)-Quinazol derivative and its preparation method and use |
| CN109553534A (en) * | 2018-11-27 | 2019-04-02 | 常州大学 | A kind of preparation method of 2- nitro -4- methoxy benzoic acid |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6136273A (en) * | 1984-07-26 | 1986-02-20 | Mitsubishi Yuka Yakuhin Kk | 2-phenylalkyl-4(3h)-quinazolinone derivative |
| US5679715A (en) | 1995-06-07 | 1997-10-21 | Harris; Richard Y. | Method for treating multiple sclerosis |
| US5783577A (en) * | 1995-09-15 | 1998-07-21 | Trega Biosciences, Inc. | Synthesis of quinazolinone libraries and derivatives thereof |
| CA2244253C (en) | 1996-03-15 | 2002-11-12 | Somerset Pharmaceuticals, Inc. | Method for preventing and treating peripheral neuropathy by administering selegiline |
| JP4959049B2 (en) * | 1997-08-22 | 2012-06-20 | アストラゼネカ・ユーケイ・リミテッド | Oxyindolylquinazoline derivatives as angiogenesis inhibitors |
| US6890930B1 (en) * | 1999-09-28 | 2005-05-10 | 3-Dimensional Pharmaceuticals, Inc. | Quinazolinones |
| WO2001034172A2 (en) | 1999-11-05 | 2001-05-17 | Vela Pharmaceuticals Inc. | Methods and compositions for treating reward deficiency syndrome |
-
2003
- 2003-12-08 KR KR1020057010696A patent/KR100707532B1/en not_active IP Right Cessation
- 2003-12-08 AT AT03789170T patent/ATE335729T1/en not_active IP Right Cessation
- 2003-12-08 RU RU2005121908/04A patent/RU2340604C2/en not_active IP Right Cessation
- 2003-12-08 ES ES03789170T patent/ES2270154T3/en not_active Expired - Lifetime
- 2003-12-08 DE DE60307512T patent/DE60307512T2/en not_active Expired - Lifetime
- 2003-12-08 CA CA002509633A patent/CA2509633A1/en not_active Abandoned
- 2003-12-08 JP JP2004559781A patent/JP4384053B2/en not_active Expired - Lifetime
- 2003-12-08 AU AU2003293798A patent/AU2003293798B8/en not_active Ceased
- 2003-12-08 EP EP03789170A patent/EP1572666B1/en not_active Expired - Lifetime
- 2003-12-08 PL PL377474A patent/PL377474A1/en not_active Application Discontinuation
- 2003-12-08 MX MXPA05006124A patent/MXPA05006124A/en active IP Right Grant
- 2003-12-08 BR BR0317282-1A patent/BR0317282A/en not_active IP Right Cessation
- 2003-12-08 CN CNB2003801052982A patent/CN100418954C/en not_active Expired - Fee Related
- 2003-12-08 WO PCT/EP2003/013888 patent/WO2004054985A1/en active IP Right Grant
- 2003-12-09 TW TW092134699A patent/TW200424180A/en unknown
- 2003-12-10 PA PA20038591901A patent/PA8591901A1/en unknown
- 2003-12-10 PE PE2003001256A patent/PE20040911A1/en not_active Application Discontinuation
- 2003-12-10 CL CL200302565A patent/CL2003002565A1/en unknown
- 2003-12-11 GT GT200300284A patent/GT200300284A/en unknown
- 2003-12-11 UY UY28120A patent/UY28120A1/en not_active Application Discontinuation
- 2003-12-11 AR ARP030104562A patent/AR042362A1/en unknown
- 2003-12-12 MY MYPI20034764A patent/MY141743A/en unknown
- 2003-12-13 US US10/734,949 patent/US7087612B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191667A (en) * | 2018-01-04 | 2018-06-22 | 利尔化学股份有限公司 | The preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters |
| CN108191667B (en) * | 2018-01-04 | 2021-03-26 | 利尔化学股份有限公司 | Preparation method of 2-nitro-4-trifluoromethyl methyl benzoate |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003293798B2 (en) | 2009-01-15 |
| GT200300284A (en) | 2004-07-14 |
| JP4384053B2 (en) | 2009-12-16 |
| JP2006513177A (en) | 2006-04-20 |
| CL2003002565A1 (en) | 2005-01-07 |
| CN100418954C (en) | 2008-09-17 |
| AU2003293798A1 (en) | 2004-07-09 |
| KR20050085587A (en) | 2005-08-29 |
| WO2004054985A1 (en) | 2004-07-01 |
| DE60307512T2 (en) | 2007-02-08 |
| CA2509633A1 (en) | 2004-07-01 |
| US7087612B2 (en) | 2006-08-08 |
| MY141743A (en) | 2010-06-30 |
| EP1572666A1 (en) | 2005-09-14 |
| ES2270154T3 (en) | 2007-04-01 |
| MXPA05006124A (en) | 2005-08-16 |
| UY28120A1 (en) | 2004-06-30 |
| TW200424180A (en) | 2004-11-16 |
| DE60307512D1 (en) | 2006-09-21 |
| EP1572666B1 (en) | 2006-08-09 |
| AU2003293798B8 (en) | 2009-02-12 |
| ATE335729T1 (en) | 2006-09-15 |
| KR100707532B1 (en) | 2007-04-12 |
| PE20040911A1 (en) | 2004-12-11 |
| US20040142951A1 (en) | 2004-07-22 |
| BR0317282A (en) | 2005-11-08 |
| RU2340604C2 (en) | 2008-12-10 |
| RU2005121908A (en) | 2006-01-27 |
| AR042362A1 (en) | 2005-06-15 |
| PL377474A1 (en) | 2006-02-06 |
| PA8591901A1 (en) | 2004-11-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1720237A (en) | 3h-quinazolin-4-one derivatives | |
| CN1215060C (en) | Condensed pyrazole compound, composition containing it and its application | |
| CN1129597C (en) | Heterocyclic compounds and antitumor agent containing the same as active ingredient | |
| CN88101642A (en) | Piperazinyl-heterogeneous ring compound | |
| CN1104422C (en) | Guanidinyl heterocycle compounds useful as alpha-2 adrenoceptor agonists | |
| CN1358175A (en) | Pyrimidinone compounds | |
| CN1028990C (en) | Hiv-inhibiting benzeneacetamide derivatives | |
| CN1301970C (en) | 2,4-substituted indoles and their use as 5-HT6 modulators | |
| CN1044094A (en) | 2-aminopyrimidinone derivatives | |
| CN1175252A (en) | Imidazole derivatives as protein kinase inhibitors in particular egf-rthyrosine kinase | |
| CN1092652C (en) | 2-imidazolinylaminoindole compounds useful as alpha-2 adrenoceptor agonists | |
| CN1274669C (en) | Fluorobenzamides suitable for the treatment of alzheimer's disease or senile dementia | |
| CN1966506A (en) | Pyrromonazole pyrimidinone derivatives, method of producing them and use thereof | |
| CN1680334A (en) | Fused pyrazolyls | |
| CN1067985C (en) | Indole derivative and medicine containing the same | |
| CN1125575A (en) | Adhesion receptor antagonists | |
| CN1074904A (en) | Benzofuryl-and thienyl methylthio group-alkanoic acid derivs | |
| CN1054249A (en) | Sulfonyl aniline derivatives and in pharmaceutically application | |
| CN1333755A (en) | Benzimidazole compounds that are vitronectin receptor antagonists | |
| CN1261414C (en) | Pyridineamido derivatives as inhibitors of monoamine oxidase (MAO-B) | |
| CN1280289C (en) | Alkoxy carbonylamino heteroaryl carboxylic acid derivatives as IP antagonists | |
| CN1849308A (en) | Thiophenylaminoimidazolines | |
| CN1993319A (en) | Benzyloxy derivatives as MAOB inhibitors | |
| CN1875016A (en) | Imidazole derivatives | |
| CN1723204A (en) | Benzoxazole derivatives and their use as adenosine receptor ligands |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080917 Termination date: 20101208 |